Multiple myeloma (MM) is a life-threatening plasma cell malignancy. MM has a prolonged clinically detectable premalignant phase called monoclonal gammopathy of undetermined significance (MGUS) that can be identified by detection of the secreted monoclonal immunoglobulin (M protein) and through the presence of an abnormal immunoglobulin kappa/lambda free light chain (FLC) ratio. Over the last 10 years we have extensively characterized the various precursor stages of MM, and conducted numerous studies establishing monoclonal elevations of FLC and abnormalities in the FLC ratio as biomarkers for diagnosis, prognosis, response assessment, and risk stratification across a spectrum of plasma cell disorders. One of the goals of this renewal is to determine why MGUS occurs, and whether polyclonal plasma cell proliferation in response to infection or inflammation plays a role in pathogenesis of MGUS, MM and related malignancies. We are also investigating the reasons for dramatic racial disparity in incidence of MM; young blacks for example have a 3-fold higher risk than whites. Our studies show that a major reason for the racial discrepancy is a marked excess in the incidence of the precursor MGUS phase in blacks. Similarly, we have uncovered a significant familial predisposition in MGUS and MM. Since MM consists of multiple unique entities from a cytogenetic standpoint, we need to determine the precise cytogenetic subtypes responsible for racial disparity and familial predisposition. Thus two fundamental questions are: 1) Can we identify biomarkers that predict risk of MM prior to the premalignant MGUS stage (precursor of the precursor stage)? 2) What are the specific cytogenetic subtypes that account for the increased risk of MM in blacks and in first degree-relatives? In Aim 1 we will determine if polyclonal elevations of serum immunoglobulin FLC are associated with an increased risk of MGUS, MM and related B cell malignancies in a large cohort of nearly 16,000 patients. In Aim 2 we will assemble and study a cohort of 800 blacks with MM to identify the specific cytogenetic subtype(s) of MM associated with increased risk of MM, and also identify predictors of response to therapy and survival. In Aim 3 we will conduct studies to identify the specific cytogenetic subtypes associated with familial predisposition in MGUS. We believe our studies are highly innovative, and will have a far-reaching impact on our understanding of the etiology of MGUS, and the cytogenetic basis for racial disparity and familial predisposition. Our studies will result in a promising biomarker to identify patients at high risk for MM and related malignancies in the general population. Aims 2 and 3 will have a major impact on the management of patients with MGUS and MM, especially African Americans and first-degree relatives or persons with MGUS.